VoE. 34, No. 11, Norlrember 1969
4-METHYLCARBOSTYRIL AND
phenyl group attached to the double bond, the signal of the proton Cis to the phenyl would be shifted almost 0.5 ppm downfield from the trans proton. On this basis, 8, having the olefinic proton at r 4.73, was assigned the trans configuration, and 9, with the olefinic proton a t 7 4.33, was assigned the cis configuration. These assignments are in agreement with those published on the homologous phenylbutene isomers? Reaction of Amide Derivatives of a-Methyl-a-butylbenzylamine (2b, 2c, and 2d) with PPA.-Amide 2b (0.20 g) was added to 12 g of PPA and stirred a t room temperature for 1 hr. The slurry was then worked up as above. The product mixture (SGN column) had the following composition (wt % as estimated from relative peak areas): 6% 8, 2% 9, 37% benzamide, 52% polymeric olefins, and 3% unreacted 2b. Optically pure 2b was treated with PPA for 15 min, following the above procedure. The product was chromatographed on neutral Woelm alumina ( c 2.3, CHCL), was raceand the recovered amide, [ a I z 4-22.9 ~ mized to theextent of 9 . 2 f 5.2y0. Amide 2c was treated with PPA for 1 hr by the procedure described above and the product mixture had the following composition: 2% 8, 7% 9, 38% polymeric olefins, and 38% unreacted 2d. Treatment of N-Neopentylpivalamide (4) with PPA.-Compound 4, mp 87-89", was prepared from neopentylamineZ6and pivalyl chloride. This amide had characteristic absorptions in the ir spectrum (CHCls) a t 3480, 2950, 1650, 1510, 1390, and 1360 cm-'. Anal. Calcd for CIDHD~NO: C, 70.12; H, 12.36; N, 8.18. Found: C, 70.07; H, 12.24; N,8.08. Amide 4 (0.180 g, 0.001 mol) was added to 3.7 g of PPA and stirred for 23 hr a t 77-80'. The reaction ww then worked up as above. Vpc analysis of the extract indicated that only starting material was present. No pivalamide was evident within the limits of detection (0.3%). Evaporation of the solvent yielded 0.10 g of 4 which was identical with an authentic sample (mixture melting point and ir spectrum). Treatment of N-Benzoyl- and N-Acetyl-1, l-diphenylmethylamine (5b and Sa) with PPA.-Amide 5b (0.355 g), mp 166-169' (lit.*6172', 166-167'), was added to 7.1 g of PPA and this mixture was stirred for 1 hr a t room temperature, then treated as in similar experiments described above. Vpc analysis (SGN column) indicated that only unreacted 5b was present. None (25) D.Y.Curtin and S. M. Gerber, J . Amer. Chem. SOC.,74, 4052 (1952). (26) I. Heilbron, "Dictionary of Organic Compounds," Oxford University Press, New York, N . Y., 1953, p 90.
t~UnS-B-METHYLCINNAMANILIDE 3263
of the expected N-alkyl cleavage products were observed within the limits of detection (0.2% total benzamide plus benzylhydrol). Evaporation of the solvent left 0.30 g of 5b which was identical with an authentic sample (mixture melting point and ir spectrum). A similar result was obtained when Sa, mp 145-148' (lit." mp 152") was treated with PPA for 1 hr at room temperature. However, treatment of 5a for 1 hr a t 78' caused considerable N-acyl fission, since large amounts of acetic anhydride were evident in the ir spectrum of the crude reaction mixture. Treatment of N-Acetyl-1-Cyclohexylethylamine(3) with PPA. -Amide 3 was prepared in quantitative yield by the catalytic hydrogenation of 2e in a Parr apparatus at 48 psig using 15% rhodium on carbon as catalyst. The (+) 3 had mp 96.5-97.5', and its spectral properties (ir and nmr) were consistent with the expected structhre. Anal. Calcd for CloHleNO: C, 70.96; H, 11.31; N , 8.27. Found: C,70.81; H, 11.19; N,8.11. Optically active 3, mp 101-102.5', [CY] 2 6 11.7' ~ (c 5.27, DMF), was prepared by hydrogenation of optically active 2c [from ( -~-cu-methylbenzylaminne,98% optically pure]. The optically active 3 (1.15 g, 0.067 mol) was added to 23 g of PPA which was stirring a t 80". The mixture was stirred for 20 hr a t SO', then worked up as above. Vpc of the chloroform extract (DFX column 200°, SGN column 200') indicated that only 3 was present. Evaporation of the solvent yielded crude 3, which after recrystallization from isopropyl ether showed no significant loss in optical activity.
Registry No.-( +) 2a, 20826-48-6; 2c, 20826-78-2; (f)3, 20826-51-1; 4, 20826-79-3; 8, 20826-49-7; 9, 20826-50-0; 10, 20826-80-6; a-methyl-a-butylbenzylamine [(*)-tartrate salt], 20858-73-5. Acknowledgment.-We thank Dr. Raymond Palmere for a generous gift of 2-phenyl-2-hexanoic acid, Mr. Robert DeSimone for some of the nmr spectra, and Dr. Jessie Gove of the American Cyanamid Co. for assistance in interpreting some of the nmr spectra. The financial assistance from Mrs. Ida Claire DeJohn and from the Nopco Chemical Co. is gratefully acknowledged. (27) A. Kalussner, S. Blum, and E. Bergmann, J . 078. Chern., 18, 3588 (1963).
Formation and Reactions of Dianions Derived from 4-Methylcarbostyril and trans-p-Methylcinnamanilidel JAMESF. WOLFE,GEORGEB. TRIM ITS IS,^^ AND DAVID R. MORRIS^^ Department of Chemisty, Virginia Polytechnic Institute, Blachburg, Virginia 84601 Received February 11, 1969
Treatment of Cmethylcarbostyril (1) with 2 mol equiv of n-butyllithium in tetrahydrofuran-hexane effected ionization of the N H proton and one of the methyl protons to form resonancestabilized dianion 2. Reaction of dianion 2 with carbonyl compounds, alkyl halides, and carbon dioxide afforded products arising from condensation of the electrophilic reagent at the exocyclic carbanion site. These reactions represent the first examples of successful carbon-carbon condensations at the methyl group of 1, a position which has previously been considered to be unreactive. trans-8-Methylcinnamanilide (12) also underwent similar twofold ionization with n-butyllithium to afford dianion 13. Protonation and alkylations of dianion 13 took place predominately a t the a-carbanion site, while condensations with benzophenone and 9-fluorenone occurred preferentially a t the terminal carbanion position.
Although Pmethylcarbostyril (1) has structural features which might be expected to impart some measure of acidity to the hydrogens of its methyl group, there appear to be no examples in the literature of reactions involving even transient carbanion formation at this (1) (a) Supported by Grant 14340 from the National Institute of General Medical Sciences. (b) Presented before the Organic Division of the American Chemical Eociety, Atlantic City, N. J., Sept 1968. (2) (a) Taken in part from the Ph.D. thesia of G . B. T., Virginia Polytechnic Inatitute, Aug 1968. (b) National Science Foundation Undergraduate Research Participant,summer 1966.
position. Indeed, failure of 1 to undergo typical carbon-carbon condensation at its methyl group has been cited as evidence that the methyl protons do not possess any appreciable active hydrogen character. We now wish to report that treatment of 1 with 2 mol equiv of n-butyllithium in tetrahydrofuran-hexane for (3) (a) R. C. Elderfield, "Heterocyclic Compounds," Vol. 4, R. C. Elderfield, Ed., John Wiley & Sons, Inc., New York, N. Y., 1952, p 150: (b) N. K . Khromor-Barisov, R. S. Kartinskaya, and L. N. Aggeva. Zh. Obehch. Khim.. %S, 2294 (1955) [Chem.Abatr., 60,94290 (1956)l.
3264 WOLFE,TRIMITSIS, AND MORRIS
The Journal of Organic Chemistry
approximately 15 min a t room temperature results in a twofold acid-base reaction in which the alkyllithium reagent abstracts the NH proton as well as a methyl proton to produce resonance-stabilized dianion 2. In-
2 C,H,Li
Interestingly, treatment of dianion 2 with ethyl acetate or acetyl chloride afforded tertiary alcohol 6,rather than the expected acetyl derivative 7. That 6 was the
.'..
THF-hexane
I
H 2
1
itial evidence for formation of dianion 2 was obtained by quenching the reaction mixture with deuterium oxide followed by nmr analysis of the resulting deuterated product. The results of the deuteration experiment were further confirmed by trapping dianion 2 with various electrophilic reagents. These reactions, which are described below, represent the first examples of active hydrogen type condensations at the methyl group of 1, and serve to demonstrate the potential synthetic utility of dianion 2. Treatment of dianion 2 with cyclohexanone and benzophenone produced tertiary alcohols 3a and 3b, respectively. Similarly, reaction of dianion 2 with anisaldehyde and isobutyraldehyde afforded secondary alcohols 3c and 3d. Alkylations of dianion 2 were effected with benzyl chloride, n-butyl bromide, and isopropyl bromide to produce 4-alkylcarbostyril derivatives 4a-c. Carboxylation of dianion 2 with excess solid carbon dioxide gave acid 5. Struct,ural assignments 3a-d, 48-c, and 5
6
"ilH
I
OQo I H
4a, R = CH2CGHS
PH
b, RamC4Hg
C,
I
9
0
C,
R = CH(CH&
II CH2CCH3 I
OH
d, R =-CHCH(CHJZ
T o
LafTerty-type rearrangement of the molecular ion of 6 in which a! cleavage is accompanied by concomitant transfer of the OH hydrogen of the alcohol function to the 3 position of the carbostyril nucleus.6 Formation of carbinol 6 undoubtedly occurs via initial reaction of the acylating agent with dianion 2 to produce monoanion 10. This intermediate then undergoes a rapid carbonyl addition' reaction with a second equivalent of dianion 2 to form trianion intermediate 11, which is converted into 6 on neutralization of the reaction mixture.
OH
I R--CHC&OCH,-p
1
H 8
I
b, R =-&XU
r
a.
CH,R
3a, R =
7
proposed dicondensation product was verified by its mass spectrum, which had a molecular ion peak at m/e 360 (2% of the base peak) along with peaks at m/e 202 (28%) and 159 (base peak). The peak at m/e 202 is presumably due to fragment 8, which results from cleavage at the a! (carbinol) carbon of the molecular ion of 6,a process which is characteristic of tertiary alc o h o l ~ . ~The fragment appearing at m/e 159 is assigned structure 9, and apparently arises from a Mc-
0-
r
5, R- COOH
were based on analyses and spectral characteristics (see Experimental Section). In particular, the nmr spectra were consistent with products arising from condensation at the exocyclic carbanion site of dianion 2. Thus, the methyl resonance, which had appeared at 2.54 ppm in the spectrum of 1, was replaced by absorption for two side-chain methylene protons with the a p propriate multiplicity in the spectra of these derivatives. Further support for the structure of acid 5 was obtained by its decarboxylation to regenerate 1.
The above results with cyclic anilide 1 prompted us to investigate the possibility of effecting similar twofold ionization of trans@-methylcinnamanilide (12), which may be regarded aa an open-chain analog of 1. Treat-
(4) For analogous examplee of dianion formation by means of n-butyllithium, which appeared while this work waa in progress, 8 8 8 (a) E. J. Corey and T. Durst, J . Amer. Chcm. SOC., 88,6666 (1966); (b) R. L. Gay and C. R. Hauser, ibid., 89, 1647 (1967); and (0) R. E. Smith, 9. Boatman. and C. R. Hauser, J . Org. Chsm., SI,2083 (1968).
the mass spectra of acyclic unsaturated alcohols. (7) Attack of dianion 4 at the carbonyl group of monoanion 10 apparently occura because the most likely alternate course of reaction, Le., abstraction of a methylene hydrogen of 10 by dianion 4, is retarded by the residual negative charge on the heterocyclic ring of 10.
L
10
11
(6) R . A. Friedel, J. L. Schult~,and H. G. Sharkey, Anal. Chem., 98, €126 (1966). (6) See H. E. Audier, H. Felkin, M. Fetiaon, and W. Vetter, Bull. SOC. Chim. Fr.,3236 (1964), for examplea of a similar fragmentation pathway in
VoZ. 34, No. 11, November 1969
~METHYLCARBOSTYRIL AND tr~ns-P-METHYLCINNAMANILIDE 3265
ment of 12 with 2 mol equiv of n-butyllithium in tetrahydrofuran-hexane ah room temperature produced dianion 13, as evidenced by its subsequent protonation and condensations with certain electrophiles.
tion of the nmr spectra of the unrefined mixtures obtained from these reactions failed to reveal the presence of any significant amounts of the possible isomeric derivatives. Therefore, the isolated products appear to be representative of the major course of reaction of dianion 13 with the respective electrophile.
Discussion 12
r
0
13
Hydrolysis of dianion 13 with water afforded the less stable, nonconjugated isomer 148and starting anilide 12 in a ratio of 2.3: 1, rn determined by nmr analysis of the crude reaction m i x t ~ r e . ~Thus, protonation of dianion 0
I
HO
13
1 . C,jH5NHCCHz(f--CHz
+
12
It seems that the rather striking dissimilarities observed in the reactions of dianion 2 and 13 with electrophilic reagents may be best rationalized in terms of different electronic distributions in their respective ?r systems. The tendency for dianion 2 to undergo reactions exclusively at its exocyclic carbanion site is consistent with a significantly higher degree of negative charge density at that position than at the potentially carbanionic 3 position. I n resonance terminology, this would mean that canonical form 17,in which the aromatic character of the heterocyclic ring is maintained and one of the charges resides on electronegative oxygen, contributes more to the hybrid structure of dianion 2 than do other forms having negative charge localized a t the 3 position. In contr& to dianion 2 , dianion 13
(30%)
a
C,H, 14 (70%)
13 followsthe Hughes--1ngoldrulelo for proton capture by allylic anions in the respect that the tautomer which is formed more rapidly is the thermodynamically less stable one. Dianion 13 also underwent alkylation with n-butyl bromide and benzyl chloride at its a-carbanion site to afford nonconjugated derivatives 15a and 15b. However, when dianion 13 was allowed to react with benzophenone and 9-fluorenone, only the terminal condensation products 16a and 16b were isolated.” Examina0
II
C6H,NHCCH-Cc\lHZ
I
R
I
C&
15a, R = n-C,HS
b, R=CH2C,H5
0 C,HSNHCCH=(iCH,R
II
C6H5 OH I 16a, R = -C(C6H5)2
b, R =
(8) The relative thermodynamic stabilities of 13 and 14 were established by treating each of them with aodium methoxide in methanol to produce the same equilibrium mixture. which consisted of 98% conjugated isomer 13 and 2% nonconjugated isomer 14. (9) The nmr s m t r u m of the crude mixture also had absorption characteristic of an n-butyl group, indicating that some conjugate addition of nbutyllithium t o the ix,#-unssturated carbonyl system of 13 had occurred. This competitive reaction a p ~ e a mto be responsible for the lower yields obtained from dianion 18 when it and dianion 3 were treated separately with the same electrophilic reagent. (10) C. K. Ingold, “Structure and Mechanism in Organic Chemistry,” Cornell University Presa, Ithaca, N. Y.,1853,p 565. For a more recent discussion of allylic anions, including n number of exceptions to the HughesIngold rule, see C. D. Broaddun, Accounts Chcm. Res., 1,231 (lQ68). (11) Both 16a and 16b had physical properties which were indicative of a single geometric isomer. Although a rigorous proof of their stereochemistry was not attempted, the absence of coupling between the methylene protons and the vinyl proton in the nmr spectra of these compounds indicates that the vinyl hydrogen and the methylene group are cia to one another. See J. R. Dyer, “A~~fi-tions of Absorption Spectroscopy of Organic Compounds,” Prentice-Hall, Inc.. Englewood Cliffs, N. J., 1965, p QQ.
0-
17
0
0
-
II -
~
II
~
#I
C,jHSN-C-CH=C-CH,
C6H5N- C-CH-
6GH6 18
I CBH5
19
undergoes protonation and alkylation predominately at its CY carbanion position because the carbon adjacent to the carbonyl group holds a greater share of the delocalized electron pair than does the terminal carbon. Thus, canonical form 18 may be said to make a greater contribution to the structure of dianion 13 than does canonical form 19. However, the terminal site of dianion 13 still has sufficient charge density to allow reactions to occur there when the steric requirements of the electrophile impede condensation at the CY position, as appears to be the case in the reactions of 13 with benzophenone and 9-fluorenone.12 The formation of allylic dianion 13 is somewhat surprising in view of a recent report that crotonanilide failed to afford an analogous dianion under similar cond i t i o n ~ . ‘ ~This failure was attributed to conjugate addition of n-butyllithium to the cr,P-unsaturated carbonyl system, a process which occurs to some extent in the case of 12. Since the phenyl substituent in 12 would be expected to have little electronic influence on either conjugate addition or proton abstraction, it appears that it exerts primarily a steric effect, thereby re(12) I t is possible that the condensations of dianion 18 with benzophenone and 9-fluorenone could involve initial kineticaliy controlled attack of the ketone a t the a pwition, followed by dissociation and reoornbination, t o form the thermodynamically more atable terminal products. However, we were unable to isolate any u-substituted derivatives, even when shorter reaotion periods and lower temperaturea were employed.
3266
WOLFE, TRIMITSIS, AND MORRIS
tarding conjugate addition and allowing proton abstraction to take place. Finally, it should be mentioned that the twofold ionization of 1 to form dianion 2 is of definite synthetic interest in that it transforms what heretofore has been regarded as an inert8substituent into a reactive carbanion site. This new reaction center permits facile modification of the original methyl group to produce a variety of 4-substituted carbostyril derivatives from a single, readily availlable precursor. l 3
Experimental Section14 Preparation of Starting Materials. A. 4-Methylcarbostyril (l).-This compound was prepared from acetoacetanilide by the method of Lauer and Kaslow16 and had mp 223-224' (lit." mp 222-224'); nmr 6 11.82 (s, 1, NH), 7.60 (m, 4, aromatic), 6.64 (s, 1, vinyl), and 2.54 jppm (s, 3, CH3). B. trans-BMethylcinnamanilide (13).--Th& compound was prepared in 52% overall yield by allowing dilithioacetanilide'b to condense with acetophenone in tetrahydrofuran (THF)hexane at room temperature. The resulting alcohol, mp 69-71' from carbon tetrachloride, was characterized spectrally and then dehydrated by refluxing it with 10% by weight of p-toluenesulfonic acid in benzene. The resulting solid was recrystallized several times from carbon tetrachloride to afford 13, mp 119121" (lit.l6 m p 121"); nmr 6 10.0 (s, 1, NH), 7.86 (m, 10, aromatic), 6.76 (q, 1, J = 2 Hz, C=CH), and 2.76 ppm (d, 3, J = 2 Hz, CH3). Preparation of 4-Methylcarbostyril Dianion (2).-To a stirred suspension of 3.98 g (0.025 mol) of 1 in 100 ml of anhydrous T H F contained in a 250-ml, three-necked, round-bottomed flask at room temperature under nitrogen, was added 38.1 ml (0.056 mol) of a 1.47 M solution of' n-butyllithium in hexane17over aperiod of 3 min to produce a dark red-brown solution. This solution was allowed to stir a t room temperature for an additional 10 min before being employed in the reactions described below. Deuteration of Dianion 2.-A solution of dianion 2 (63 mmol) in 20 ml of THF-hexane was prepared as described above. The reaction mixture was then poured into 10 ml of deuterium oxide to produce a heavy white precipitate, which quickly dissolved. The resulting mixture was stirred for 50 rnin and then concentrated to dryness under reduced pressure. The residual solid was washed with 10 ml of deuterium oxide and dried to afford 0.94 g (94%) of 1 4 , mp 220-222', mmp with a sample of I-&, 221-222"; nmr 6 7.96 (m, 4, aromatic) 6.98 (s, 1, vinyl), and 2.60 ppm (s, 2.1, CHJ)). The integrated intensity of the CH2D peak compared with that of the aromatic multiplet or the vinyl singlet was consistent with incorporation of 0.9 of one deuterium atom a t the methyl position. The spectrum of the deuterated product was devoid of N H resonance. When dianion 2 was quenched with water, a comparable yield of 1 was recovered and no isomeric products were detected. In order to verify that deuteration a t the methyl position of 1 (13) For a discussion 01' a less direct, but widely used procedure for the synthesis of 4-substituted carbostyrils, see B. Staskun, J . Ore. Chem., 09, 1153 (1964). (14) Melting points were taken on a Thomas-Hoover melting point apparatus in open capillary tubes and are corrected. Analyses were performed by Galbraith Laboratories, Knoxville, Tenn., and in our laboratories by Miss Q. H. Tan using an F & M Model 185 C, H. and N analyzer. Infrared spectra were taken on a Beckman IR-JA spectrophotometer using the potassium bromide pellet method. Nmr spectra were determined with a Varian Associates A-60 spectrometer using DMSO-& as the solvent for all compounds except 14. 14, and 16% where acetone-& was employed. Chemical shifts, relative to internal tetramethylsilane. are measured to the center of a singlet or multiplet. Mess spectra were obtained on a Perkin-Elmer Hitachi RMU spectrometer at 50 eV. Gas chromatograms were obtained on a Varian Aerograph Model 1200-1 gas chromatograph using a 5 ft X '/a in. 5% SE-30 (Methyl) on 60/80 DMCS Chromoeorb W column with nitrcgen as the carrier gas. Unless otherwise specified, chemicals were commercial reagent grade and were used without further purification. (15) W. M. Lauer and 0.E. Kaslow, "Organic Syntheses," Coll. Vol. 111, E. C. Horning, Ed., John W l e y & Sons, Inc., New York, N . Y., 1955, p 58. (16) F. Henrich and A. Wirth. Chem. Bet., 57, 732 (1904). (17) This reagent was obtained from Foote Mineral Co., Exton, Pa., and was standardized by the procedure of H. Gilman and A. H. Haubein, J . Amer. Chem. Soc., 66, 1515 (1944).
The Journal of Organic Chemistry had occurred through dianion 2 and not v i a exchange catalyzed by the lithium deuteroxide formed in the quenching experiment, a 0.5-g (3-mmol) sample of 1 in 10 ml of T H F was treated with 0.14 mol of lithium deuteroxide, prepared from 0.14 g-atom of lithium metal in 5 ml of deuterium oxide, for 1 hr. The reaction mixture was processed as described above to afford a nearly quantitative recovery of 1 4 , the nmr spectrum of which showed no NH resonance. The integrated intensity of the methyl protons was undiminished. Carbonyl Addition Reactions of Dianion 2.-These reactions were carried out using 0.025 mol of dianion 2 in 100 ml of THF, to which was added 0.037 mol of the appropriate aldehyde or ketone in 30 ml of T H F over a period of 1-5 min. Additional details are given below. A. Cyclohexanone.-Addition of the ketone to dianion 2 produced a thick precipitate, which dissolved in a few minutes to produce a light yellow solution. The reaction mixture was allowed to stir for l hr, and was then poured into 200 ml of icewater. The two-phase mixture was allowed to warm to room temperature and the THF-hexane was removed on a rotary evaporator. The resulting aqueous solution was allowed to stand overnight in the refrigerator to produce a precipitate, which was collected and recrystallized from aqueous ethanol to afford 6.4 g (87%) of 4-(l-hydroxycyclohexylmethyl)carbostyril (3a), mp 182-184'; ir 3100-3450 (NH and OH) and 1630 cm-l(C=O); nmr 6 12.06 (8,1, NH), 7.76 (m, 4, aromatic), 6.66 (9, 1, vinyl), 4.34 (s, 1, carbinol OH18),3.00 (9, 2, side-chain CH,), and 1.52 ppm (broads, 10, cyclohexyl). Anal. Calcd for ClsHtgNO2: C, 74.68; H, 7.44; N, 5.44. Found: C, 74.92; H, 7.51; N, 5.34. B. Benzophenone.-This reaction was carried out as described for the condensation with cyclohexanone, except that, after the organic solvents had been removed, the remaining aqueous solution was made weakly acidic with cold 6 N HCl. The resulting precipitate was recrystallized from a large volume of absolute ethanol to give 6.3 g (74%) of 4-(2,2-diphenyl-2-hydroxyethy1)carbostyril (3b), m p 281-283'; ir 3125-3450 (NH and OH) and 1640 cm-' ( C = O ) ; nmr 6 12.16 (s, 1, NH), 7.88 (m, 14, aromatic), 6.70 (s, 1, vinyl), 6.30 (s, 1, carbinol OH), and 5.2 ppm (s, 2, side-chain CHZ). Anal. Calcd for C23HlgNO: C, 80.95; H, 5.57; N, 4.11. Found: C,80.77; H, 5.71; N,4.27. C. Anisaldehyde.-Dianion 2 was prepared at room temperature and then cooled to 0' in an ice-salt bath. A solution of anisaldehyde in T H F was added over a period of 1 min and the reaction mixture was allowed to stir for 5 min at Oolo before being poured into 200 mi of cold 6 N HCl. The layers were separated and the aqueous layer was diluted with 200 ml of cold water and allowed to stir for 30 min. The resulting precipitate was recrystallized from absolute ethanol to give 3.46 g (47%) of 4- [2-hydroxy-2-(p-methoxyphenyl)ethyl]carbostyril (Jc), mp 230-231'; ir 3025-3380 (NH and OH) and 1630 cm-' (C=O); nmr 6 11.92 (5, 1, NH), 7.50 (m, 8, aromatic), 6.50 ( s , 1, vinyl), 5.60 (d, 1, carbinol OH), 5.06 (m, 1, carbinol CH), 3.84 (s, 3, OCHa), and 3.22 ppm (d, 2, side-chain CHz). Anal. Calcd for C&nNOs: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.46; H , 5.88; N, 4.61. D. 1sobutyraldehyde.-Tb reaction was carried out essentially as described for the anisaldehyde condensation. The crude product was recrystallized from aqueous ethanol to yield 2.58 g (50%) of 4-(2-hydroxy-3-methylbutyl)carbostyril(Jd), mp 169-171'; ir 3125-3390 (NH and OH) and 1630 cm-1 ( ( 2 4 ) ; nmr 6 12.42 (s, 1, NH), 7.86 (m, 4, aromatic), 6.86 (s, 1, vinyl), 4.70 (d, 1, carbinol OH), 3.72 (m, 1, carbinol CH), 3.02 (d, 2, side-chain CHt), 1.8 (m, 1, isopropyl CH), and 1.02 P P [d, ~ 6, W H a k l . Anal. Calcd for ClrH17N02: C, 72.70; H, 7.41; N, 6.10. Found: C, 72.97; H, 7.37; N,5.89. Alkylations of Dianion 2 .-These reactions were accomplished by adding a solution of 0.037 mol of the appropriate alkyl halide in 25-30 ml of T H F to 0.025 mol of dianion 2 in 100 ml of THF a t room temperature. Reaction mixtures were processed as in (18) Carbinol OH protons were identified by shaking the nmr samples with a few drops of deuterium oxide and then rescanning the spectrum to observe which of the original peake bad disappeared. This procedure also led to exchange of the N H proton of the carbostyril nucleus. (19) When the reaction was allowed to proceed for 1 hr at room temperature, unchanged 1 was recovered, and none of the desired alcohol could be isolated.
Vol. 84, No. 11, Nov
